Poly(ADP-ribose) polymerase (PARP) is an attractive antitumor target because of its vital role in DNA repair. Many anti-cancer therapies, including alkylating agents and radiation, produce DNA strand breaks and PARP is an essential player in the repair of this type of DNA damage. PARP inhibitors have emerged as a promising therapeutic class of compounds, and numerous PARP inhibitors have advanced into clinical trials.
The homologous recombination (HR) DNA repair pathway is critical for the repair of DNA double-strand breaks. HR deficiency leads to a dependency on error-prone DNA repair mechanisms, with consequent genomic instability and oncogenesis. Tumor-specific HR defects may be exploited through a synthetic lethal approach for the application of anticancer therapeutics, including PARP inhibitors. The demonstration of single-agent antitumor activity of PARP inhibitors in cancers with deficiencies in breast cancer susceptibility BRCA1 and BRCA2 provides strong evidence for the clinical application of this approach. Mutations in the BRCA1/2 genes are associated with HR-mediated double strand break repair defects, and inhibition of the base-excision repair-mediated single strand break repair via PARP inhibition results in synthetic lethality. For example, olaparib (AZD-2281/KU-0059436, Astra Zeneca) is a phthalazinone PARP inhibitor that is in phase II clinical trials as an oral single agent for the treatment of BRCA-deficient breast and ovarian cancers (Vasiliou at al., Drugs Future, 34: 101-105 (2009)).
Nitric oxide (NO) is a signaling molecule, a toxicant, and an antioxidant under various conditions, with a broad spectrum of actions in physiological and pathological processes. Diazeniumdiolate-based nitric oxide-releasing prodrugs are a growing class of promising NO-based cancer therapeutics. O2-(2,4-Dinitrophenyl)-1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K) has proven effective against leukemia, multiple myeloma, prostate, liver, and non-small cell lung cancer (NSCLC) cancer cell lines in vitro and in vivo (see, e.g., Shami et al., Mol. Cancer Ther., 2: 409-417 (2003); Shami et al., J. Med. Chem., 49: 4356-4366 (2006); Kiziltepe et al., Blood, 110: 709-718 (2007); and Maciag et al., J. Pharmacol. Exp. Ther., 336: 313-320 (2011)).
Thus, even though current therapies exist, there is an unmet need for agents suitable for treating cancers, particularly agents that can both damage DNA and inhibit DNA repair in cancer cells.